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Objective: To investigate whether there is an association between endometriosis and nongynecological diseases in the general female population by age 50? Design: A prospective cohort study. Setting: Study participants with and without endometriosis were identified from a general population-based birth cohort. The analyzed data, linking to the national hospital discharge registers, spanned up to the age of 50 years. Patient(s): Endometriosis case identification was based on national register data and self-reported diagnoses, producing a study population of 349 women with endometriosis and 3,499 women without endometriosis. Main outcome measure(s): International Classification of Diseases diagnosis codes from 1968 to 2016 were accumulated from the Finnish national Care Register for Health Care, whereas self-reported symptoms and continuous medication usage data were collected from the questionnaires distributed at age 46. The associations between endometriosis and comorbidities were assessed using logistic regression models that included several covariates. The odds ratios and 95% confidence intervals (CIs) were modeled. Endometriosis subtype and temporal analyses were also performed. Result(s): Women with endometriosis were on average twice as likely to have hospital-based nongynecological diagnoses as women without endometriosis (adjusted odds ratio [aOR] 2.32; 95% CI, 1.07–5.02). In more detail, endometriosis was associated with allergies, infectious diseases, pain-causing diseases, and respiratory diseases. Moreover, the affected women presented with nonspecific symptoms and signs (aOR 3.56; 95% CI, 2.73–4.64), especially abdominal and pelvic pain (aOR 4.33; 95% CI, 3.13–4.76) more often compared with nonendometriosis controls. The temporal analysis revealed that diagnoses accumulated at a significantly younger age among women with endometriosis than in nonendometriosis counterparts. Conclusion(s): Women with endometriosis have a high risk for several chronic diseases compared with women without endometriosis, underlying the need for awareness and targeted resources for these women in the health care system. Moreover, endometriosis should be considered in the presence of nonspecific symptoms and abdominal pain, as they may conceal the disease and cause considerable delay in diagnosis and treatment.

BACKGROUND: Adverse pregnancy outcomes (APO) contribute to higher risk of maternal cerebrovascular disease, but longitudinal data that include APO and stroke timing are lacking. We hypothesized that APO are associated with younger age at first stroke, with a stronger relationship in those with >1 pregnancy with APO. METHODS: We analyzed longitudinal Finnish nationwide health registry data from the FinnGen Study. We included women who gave birth after 1969 when the hospital discharge registry was established. We defined APO as a pregnancy affected by gestational hypertension, preeclampsia, eclampsia, preterm birth, small for gestational age infant, or placental abruption. We defined stroke as first hospital admission for ischemic stroke or nontraumatic intracerebral or subarachnoid hemorrhage, excluding stroke during pregnancy or within 1 year postpartum. We used Kaplan-Meier survival curves and multivariable-adjusted Cox and generalized linear models to assess the relationship between APO and future stroke. RESULTS: We included 144 306 women with a total of 316 789 births in the analysis sample, of whom 17.9% had at least 1 pregnancy with an APO and 2.9% experienced an APO in ≥2 pregnancies. Women with APO had more comorbidities including obesity, hypertension, heart disease, and migraine. Median age at first stroke was 58.3 years in those with no APO, 54.8 years in those with 1 APO, and 51.6 years in those with recurrent APO. In models adjusted for sociodemographic characteristics and stroke risk factors, risk of stroke was greater in women with 1 APO (adjusted hazard ratio, 1.3 [95% CI, 1.2–1.4]) and recurrent APO (adjusted hazard ratio, 1.4 [95% CI, 1.2–1.7]) compared with those with no APO. Women with recurrent APO had more than twice the stroke risk before age 45 (adjusted odds ratio, 2.1 [95% CI, 1.5–3.1]) compared with those without APO. CONCLUSIONS: Women who experience APO have earlier onset of cerebrovascular disease, with the earliest onset in those with more than 1 affected pregnancy.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting 8%-13% of reproductive-aged women. The aetiology of the syndrome is complex, with genetic susceptibility, androgen exposure in early life and adiposity related dysfunction leading to perturbance in hypothalamic-ovarian function. PCOS clinical features are heterogeneous, with manifestations arising even in early adolescence, developing into multisystem reproductive, metabolic and psychological manifestations in adulthood. In this review, we will discuss challenges in the diagnosis of PCOS and understanding of the natural history of PCOS.

Introduction and hypothesis This study was aimed at investigating the long-term effectiveness of minimally invasive mid-urethral sling (MUS) surgery and at comparing the outcomes between retropubic (tension-free vaginal tape, TVT) and transobturator tape (TOT) methods in the treatment of stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) with a predominant stress component in a long-term follow-up of a randomized controlled trial. Methods This work is a long-term follow-up study of a previous prospective randomized trial conducted in the Department of Obstetrics and Gynecology at Oulu University Hospital between January 2004 and November 2006. The original 100 patients were randomized into the TVT (n=50) or TOT (n=50) group. The median follow-up time was 16 years, and the subjective outcomes were evaluated using internationally standardized and validated questionnaires. Results Long-term follow-up data were obtained from 34 TVT patients and 38 TOT patients. At 16 years after MUS surgery, the UISS significantly decreased from a preoperative score in the TVT (11.88 vs 5.00, pp Conclusion Midurethral sling surgery had good long-term outcomes in the treatment of SUI and MUI with a predominant stress component. The subjective outcomes of the TVT and TOT procedures were similar after a 16-year follow-up.

This clinical trial aims to compare hormonal and metabolic changes after a 9-week continuous use of oral or vaginal combined hormonal contraceptives (CHCs) in women with polycystic ovary syndrome (PCOS). We recruited 24 women with PCOS and randomized them to use either combined oral (COC, n = 13) or vaginal (CVC, n = 11) contraception. At baseline and 9 weeks, blood samples were collected and a 2 h glucose tolerance test (OGTT) was performed to evaluate hormonal and metabolic outcomes. After treatment, serum sex hormone binding globulin (SHBG) levels increased (p < 0.001 for both groups) and the free androgen index (FAI) decreased in both study groups (COC p < 0.001; CVC p = 0.007). OGTT glucose levels at 60 min (p = 0.011) and AUCglucose (p = 0.018) increased in the CVC group. Fasting insulin levels (p = 0.037) increased in the COC group, and insulin levels at 120 min increased in both groups (COC p = 0.004; CVC p = 0.042). There was a significant increase in triglyceride (p < 0.001) and hs-CRP (p = 0.032) levels in the CVC group. Both oral and vaginal CHCs decreased androgenicity and tended to promote insulin resistance in PCOS women. Larger and longer studies are needed to compare the metabolic effects of different administration routes of CHCs on women with PCOS.

ObjectiveTo evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen.Study designWe pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes.ResultsWe included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event.ConclusionE4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns.Implications statementMost estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

Author(s): Gemzell-Danielsson, K; Apter, D; Zatik, J; Weyers, S; Piltonen, T; Suturina, L; Apolikhina, I; Jost, M; Creinin, MD; Foidart, J-M | Abstract: ObjectivesTo assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15nmg and drospirenone (DRSP) 3nmg.DesignMulticenter, open-label, phase 3 trial.SettingSixty-nine sites in Europe and Russia.PopulationSexually active women aged 18-50nyears with regular menstrual cycles and body mass index ≤35nkg/m2 .MethodsE4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary.Main outcome measuresPearl Index (PI) for women 18-35nyears (overall and method-failure), bleeding pattern and AEs.ResultsA total of 1553 women aged 18-50nyears, including 1353 from 18 to 35nyears old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5ndays per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to l16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events.ConclusionE4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile.Tweetable abstractA phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

STUDY QUESTION Can a combination of the focussed protein kinase assays and a wide-scale proteomic screen pinpoint novel, clinically relevant players in decidualization in vitro and in vivo? SUMMARY ANSWER Rho-dependent protein kinase (ROCK) activity is elevated in response to the combined treatment with progesterone and 8-Br-cAMP during in vitro decidualization, mirrored by increase of ROCK2 mRNA and protein levels and the phosphorylation levels of its downstream target Cofilin-1 (CFL1) in secretory versus proliferative endometrium. WHAT IS KNOWN ALREADY Decidualization is associated with extensive changes in gene expression profile, proliferation, metabolism and morphology of endometrium, yet only a few underlying molecular pathways have been systematically explored. In vitro decidualization of endometrial stromal cells (ESCs) can be reportedly induced using multiple protocols with variable physiological relevance. In our previous studies, cyclic AMP (cAMP)/cAMP-dependent protein kinase (PKA)/prolactin axis that is classically upregulated during decidualization showed dampened activation in ESCs isolated from polycystic ovary syndrome (PCOS) patients as compared to controls. STUDY DESIGN, SIZE, DURATION In vitro decidualization studies were carried out in passage 2 ESCs isolated from controls (N = 15) and PCOS patients (N = 9). In parallel, lysates of non-cultured ESCs isolated from proliferative (N = 4) or secretory (N = 4) endometrial tissue were explored. The observed trends were confirmed using cryo-cut samples of proliferative (N = 3) or secretory endometrium (N = 3), and in proliferative or secretory full tissue samples from controls (N = 8 and N = 9, respectively) or PCOS patients (N = 10 for both phases). PARTICIPANTS/MATERIALS, SETTING, METHODS The activities of four target kinases were explored using kinase-responsive probes and selective inhibitors in lysates of in vitro decidualized ESCs and non-cultured ESCs isolated from tissue at different phases of the menstrual cycle. In the latter lysates, wide-scale proteomic and phosphoproteomic studies were further carried out. ROCK2 mRNA expression was explored in full tissue samples from controls or PCOS patients. The immunofluorescent staining of phosphorylated CFL1 was performed in full endometrial tissue samples, and in the in vitro decidualized fixed ESCs from controls or PCOS patients. Finally, the cellular migration properties were explored in live in vitro decidualized ESCs. MAIN RESULTS AND THE ROLE OF CHANCE During in vitro decidualization, the activities of PKA, protein kinase B (Akt/PKB), and ROCK are increased while the activity of casein kinase 2 (CK2) is decreased; these initial trends are observable after 4-day treatment (P LARGE SCALE DATA Proteomic and phosphoproteomic data are available via ProteomeXchange with identifier PXD026243. LIMITATIONS, REASONS FOR CAUTION The number of biological samples was limited. The duration of protocol for isolation of non-cultured ESCs from tissue can potentially affect phosphorylation pathways in cells, yet the possible artefacts were minimized by the identical treatment of proliferative and secretory samples. WIDER IMPLICATIONS OF THE FINDINGS The study demonstrated the benefits of combining the focussed kinase activity assay with wide-scale phosphoproteomics and showed the need for detailed elaboration of the in vitro decidualization protocols. ROCK was identified as the novel target of interest in decidualization, which requires closer attention in further studies—including the context of decidualization-related subfertility and infertility. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Estonian Ministry of Education and Research, and the Estonian Research Council (PRG1076, PRG454, PSG230 and PSG608), Enterprise Estonia (EU48695), Horizon 2020 innovation grant (ERIN, Grant no. EU952516) of the European Commission, the COMBIVET ERA Chair, H2020-WIDESPREAD-2018-04 (Grant agreement no. 857418), the Academy of Finland (Project grants 315921 and 321763), the Finnish Medical Foundation and The Sigrid Juselius Foundation. The authors confirm that they have no conflict of interest with respect to the content of this article.

Introduction Endometriosis may cause a deterioration of daily functioning due to related symptoms such as pain, fatigue and psychological distress. Accordingly, endometriosis may jeopardize work ability, as suggested in mainly survey-based case-control studies, including clinically established cases at fertile age. This is the first general population-level study to evaluate how endometriosis is associated with (1) self-rated work ability and sick leave dates at age 46 years, (2) registered disability and unemployment days between age 46 and 48 and (3) lifelong emergence of registered disability retirement up to age 52. Material and methods Endometriosis case identification was based on the Care Register for Health Care and self-reported diagnosis from a population-based birth cohort, which covers 96% of children born in Northern Finland in 1966. A total of 348 women with endometriosis and 3487 women without endometriosis were identified. Questionnaire data on Work Ability Index Score was collected at age 46. Unemployment and disability days were determined from the Social Insurance Institution of Finland and the Finnish Center for Pensions registers. Finally, each individual's first-ever granted pension decision and diagnoses were collected until age 52 years. The associations between endometriosis and work ability were assessed using logistic regression models. Results Endometriosis was associated with poor work ability at age 46 (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.06-2.47). Furthermore, the association between endometriosis and over 10 days of absenteeism was increased (OR 1.53; 95% CI 1.05-2.23). Between ages 46 and 48, women with endometriosis had 10 days more disability days (55.5 vs 45.5, p = 0.030) in comparison to women without endometriosis, but 20 days less unemployment days (40.6 vs 59.2 days, p = 0.013). There were no differences in early retirement between the study groups until age 52. Conclusions Our study showed that endometriosis associates with poor work ability at age 46. Women with endometriosis have more disability days. However, their employment rate and risk of early retirement are comparable to those of women without endometriosis at late fertile age.

STUDY QUESTION Are children of mothers with polycystic ovary syndrome (PCOS) or anovulatory infertility at increased risks of obesity or diabetes? SUMMARY ANSWER Maternal PCOS/anovulatory infertility is associated with an increased risk of offspring obesity from early age and diabetes in female offspring from late adolescence. WHAT IS KNOWN ALREADY Women with PCOS often have comorbid metabolic disorders such as obesity and diabetes, and children of mothers with PCOS have an increased risk of subtle signs of cardiometabolic alterations. STUDY DESIGN, SIZE, DURATION This was a nationwide cohort study of all live births (n = 1 105 997) during 1996–2014 in Finland, excluding those with maternal diagnoses sharing signs and symptoms with PCOS (n = 8244). A total of 1 097 753 births were included and followed up until 31 December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS National registries were linked to identify births with maternal PCOS or anovulatory infertility (n = 24 682). The primary outcomes were diagnoses of obesity (ICD-10: E65, E66) and diabetes (ICD-10: E10–E14) in offspring recorded in the Finnish Care Register for Health Care. Cox proportional hazards regression was modeled to analyze the risk of offspring obesity and diabetes in relation to prenatal exposure to maternal PCOS/anovulatory infertility. Differently adjusted models and stratified analyses were used to assess whether the risk was modified by maternal obesity or diabetes diagnoses, pre-pregnancy BMI, fertility treatment or perinatal problems. MAIN RESULTS AND THE ROLE OF CHANCE Exposure to maternal PCOS/anovulatory infertility was associated with a higher cumulative incidence of obesity in the children (exposed: 1.83%; 95% CI 1.66–2.00% vs unexposed: 1.24%; 95% CI 1.22–1.26%). Accounting for birth factors and maternal characteristics such as obesity and diabetes diagnoses, the hazard ratio (HR) for obesity was increased in offspring below 9 years of age (HR 1.58; 95% CI 1.30–1.81), and in those 10–16 years of age (HR 1.37; 95% CI 1.19–1.57), but not in those aged 17–22 years (HR 1.24; 95% CI 0.73–2.11). Sex-stratified analyses revealed similar risk estimates for boys (HR 1.48; 95% CI 1.31–1.68) and girls (HR 1.45; 95% CI 1.26–1.68). Notably, the joint effect of PCOS/anovulatory infertility and BMI-based pre-pregnancy obesity on offspring obesity (HR 8.89; 95% CI 7.06–11.20) was larger than that of either PCOS/anovulatory infertility or obesity alone. Furthermore, PCOS/anovulatory infertility was associated with offspring obesity in children without perinatal problems (HR 1.27; 95% CI 1.17–1.39), with larger effect size for maternal PCOS/anovulatory infertility and joint perinatal problems (HR 1.61; 95% CI 1.35–1.91). However, the risk estimates were comparable between maternal PCOS/anovulatory infertility with (HR 1.54; 95% CI 1.17–2.03) and without fertility treatment (HR 1.46; 95% CI 1.32–1.61). For offspring diabetes, the HR was increased only between 17 and 22 years of age (HR 2.06; 95% CI 1.23–3.46), and specifically for Type 1 diabetes in females (HR 3.23; 95% CI 1.41–7.40). LIMITATIONS, REASONS FOR CAUTION The prevalence of PCOS/anovulatory infertility in this study was 2.2%, lower than that reported in previous studies. In addition, the incidence of obesity in offspring was lower than that reported in studies based on measured or self-reported weight and height and may include mainly moderate and severe obesity cases who needed and/or actively sought medical care. Moreover, mothers with PCOS/anovulatory infertility were identified based on ICD codes, with no information on PCOS phenotypes. Furthermore, maternal pre-pregnancy BMI was available only from 2004. The PCOS/anovulatory infertility association with female offspring diabetes was based on only a few cases. Mothers’ weight gain during pregnancy, use of fertility treatment other than fresh or frozen IVF/ICSI, offspring lifestyle, as well as fathers’ age, medical disorders or medication prescriptions were not available for this study. WIDER IMPLICATIONS OF THE FINDINGS These findings support that prenatal PCOS/anovulatory infertility exposure influences metabolic health in the offspring from early age. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by Shandong Provincial Natural Science Foundation, China [ZR2020MH064 to X.C.], Shandong Province Medical and Health Technology Development Plan [2018WS338 to X.C.], the joint research funding of Shandong University and Karolinska Institute [SDU-KI-2019-08 to X.C. and C.L.], the Finnish Institute for Health and Welfare: Drug and Pregnancy Project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 and SLL20190589 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. received grants from the China Scholarship Council at the beginning of the study. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER N/A.

STUDY QUESTIONHow accurately can a targeted gene expression sequencing assay estimate endometrial receptivity corresponding to the window of implantation?DESIGNEndometrial biopsies (n=175) from healthy fertile volunteers (n=66), polycystic ovarian syndrome (PCOS) patients (n=39), and recurrent implantation failure (RIF) patients (n=44) were collected and sequenced with TAC-seq (Targeted Allele Counting by sequencing) method targeting 68 biomarker genes for endometrial receptivity. The expressional profiles were clustered, and differential expression analysis was performed on the model development group, using 63 endometrial biopsies spanning over proliferative (PE, n=18), early-secretory (ESE, n=18), mid-secretory (MSE, n=17) and late-secretory (LSE, n=10) endometrial phases. A quantitative predictor model was trained on the development group and validated on sequenced samples from healthy women, consisting of 52 paired samples taken from ESE and MSE phases and five LSE phase samples from 31 individuals. Finally, the developed test was applied to 44 MSE phase samples gathered from a study group of patients diagnosed with RIF.RESULTSThe developed assay successfully captures the unique receptivity profile of the endometrium using 68 biomarker genes. When compared to healthy women of the same cycle phase, we did not detect any significant gene expression bias caused by PCOS in PE, ESE, MSE, and LSE samples. In validation samples (n=57), we detected displaced WOI in 1.8% of the samples from fertile women. In the RIF study group, we detected a significantly higher proportion of the samples with shifted WOI than in the validation set of samples from fertile women, 15.9% and 1.8%, respectively.CONCLUSIONSThe developed beREADY screening test enables highly sensitive and dynamic detection of selected transcriptome biomarkers, providing a quantitative and accurate prediction of endometrial receptivity status for personalised embryo transfer.

Investing in clinical research and evidence-based medicine has helped to improve the care for women with polycystic ovary syndrome (PCOS). However, several important questions remain unanswered on the optimal prevention and management strategies for PCOS. Addressing this uncertainty is often hindered by suboptimal research conduct leading to inefficient evidence synthesis and research wastage. PCOS research is often practised by varied specialized teams in silo leading to disharmonious and fragmented efforts neglecting the lifelong impact of PCOS on women’s wellbeing. Poor engagement among key stakeholders and lay consumers continues to limit the impact and benefits of research to society. Selective reporting on surrogate outcomes with a ‘significant’ P-value is a common malpractice in PCOS outputs. Effective adoption of the harmonizing research outcomes for PCOS (HARP) core outcome set is needed to minimize heterogeneity in reporting and promote research excellence. Small single-centre studies offer limited value to assess the varied PCOS phenotypes. Efficient large scale data-sharing is needed to address complex research questions and glean the benefits of big data research. We propose a roadmap to address these challenges and remedy future research need by promoting patient and public involvement in PCOS research to guide research efforts and address real patients’ needs; engaging all key stakeholder groups to promote a multi-disciplinary lifelong approach to new research; continuously refining research needs and priorities to revise the knowledge gap and allocate resources judiciously; standardizing outcomes definitions and measurement tools to harmonize reporting and promote excellence in research; and by investing in large data-sharing infrastructure to facilitate big data research and govern ethical data sharing.

Objective The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial. Design The study is a prospective longitudinal population-based cohort study. Methods The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884). Results In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3–3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1–9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3–3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5–13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2–3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status. Conclusions CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine disorders in women and despite this, diagnostic challenges, delayed diagnosis, and less-than-optimal treatment regimens plague the condition. The International PCOS network, consisting of geographically diverse international experts in PCOS as well as consumers, engaged in a multi-year international evidence-based guideline development process that was jointly sponsored by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM). The guideline was published in 2018 and endorsed by more than 40 international societies involved in PCOS. Translation of this evidence-based guideline to medical practice and consumer groups remains a priority. However, there remain many challenges to both understanding the diagnosis and treatment of PCOS. Evidence suggests that both clinicians and consumers are not satisfied with the timeliness of diagnosis and treatment options. This review summarizes the important findings for diagnosis and treatment from the guidelines and expands on recent developments in the literature since its publication. Special attention to diagnosis at the ends of the reproductive spectrum are discussed and remaining areas of controversy are noted. Additionally, the review highlights some of the remaining challenges in the understanding and management of PCOS to help guide clinicians and investigators in this perplexing condition.

STUDY QUESTION Is maternal polycystic ovary syndrome (PCOS) associated with increased risks for a broad spectrum of psychiatric and mild neurodevelopmental disorders in offspring? SUMMARY ANSWER Maternal PCOS and/or anovulatory infertility is independently, and jointly with maternal obesity, perinatal problems, cesarean delivery and gestational diabetes, associated with increased risks in offspring for almost all groups of psychiatric and mild neurodevelopmental disorders with onset in childhood or adolescence. WHAT IS KNOWN ALREADY Maternal PCOS was previously associated with autism spectrum disorder, attention-deficit/hyperactivity disorders and possibly developmental delay in offspring. Few studies have investigated the association between maternal PCOS and other psychiatric and neurodevelopmental disorders in offspring. STUDY DESIGN, SIZE, DURATION This was a population-based cohort study in Finland including all live births between 1996 and 2014 (n = 1 105 997). After excluding births to mothers with symptoms similar to PCOS, a total of 1 097 753 births by 590 939 mothers remained. Children were followed up until 31 December 2018, i.e. up to the age of 22 years. PARTICIPANTS/MATERIALS, SETTING, METHODS National registries were used to link data of the included births and their mothers. Data from 24 682 (2.2%) children born to mothers with PCOS were compared with 1 073 071 (97.8%) children born to mothers without PCOS. Cox proportional hazards modeling was used to evaluate the hazard ratio (HR) and 95% CI for the risk of neuropsychiatric disorders in relation to maternal PCOS. Stratified analyses were performed to test the independent role of PCOS and the joint effects of PCOS with maternal obesity, perinatal problems, cesarean delivery, gestational diabetes and use of fertility treatment. The analysis was adjusted for maternal age, country of birth, marriage status at birth, smoking, parity, psychiatric disorders, prescription of psychotropic N05/N06 during pregnancy and systemic inflammatory diseases when applicable. MAIN RESULTS AND THE ROLE OF CHANCE A total of 105 409 (9.8%) children were diagnosed with a neurodevelopmental or psychiatric disorder. Firstly, maternal PCOS was associated with any psychiatric diagnosis (HR 1.32; 95% CI 1.27–1.38) in offspring. Particularly, the risk was increased for sleeping disorders (HR 1.46; 95% CI 1.27–1.67), attention-deficit/hyperactivity disorders and conduct disorders (HR 1.42; 95% CI 1.33–1.52), tic disorders (HR 1.42; 95% CI 1.21–1.68), intellectual disabilities (HR 1.41; 95% CI 1.24–1.60), autism spectrum disorder (HR 1.40; 95% CI 1.26–1.57), specific developmental disorders (HR 1.37; 95% CI 1.30–1.43), eating disorders (HR 1.36; 95% CI 1.15–1.61), anxiety disorders (HR 1.33; 95% CI 1.26–1.41), mood disorders (HR 1.27; 95% CI 1.18–1.35) and other behavioral and emotional disorders (ICD-10 F98, HR 1.49; 95% CI 1.39–1.59). In short, there was no significant difference between sexes. The results were robust when restricting the analyses to the first-born children or births to mothers without psychiatric diagnosis or purchase of psychotropic medication. Secondly, stratified analysis according to maternal BMI showed that the risk of any neuropsychiatric disorder was increased in offspring to normal-weight mothers with PCOS (HR 1.20; 95% CI 1.09–1.32), and markedly higher in those to severely obese mothers with PCOS (HR 2.11; 95% CI 1.76–2.53) compared to offspring to normal-weight mothers without PCOS. When excluding perinatal problems, mothers with PCOS were still associated with increased risks of any neuropsychiatric disorders in offspring (HR 1.28; 95% CI 1.22–1.34) compared to mothers without PCOS. However, an additional increase was observed for PCOS in combination with perinatal problems (HR 1.99; 95% CI 1.84–2.16). Likewise, excluding cases with maternal gestational diabetes (HR 1.30; 95% CI 1.25–1.36), cesarean delivery (HR 1.29; 95% CI 1.23–1.35) or fertility treatment (HR 1.31; 95% CI 1.25–1.36) did not eliminate the associations. LIMITATIONS, REASONS FOR CAUTION The register-based prevalence of PCOS was lower than previously reported, suggesting that this study may capture the most severe cases. To combine anovulatory infertility with PCOS diagnosis as PCOS exposure might introduce diagnostic bias. It was not feasible to distinguish between subtypes of PCOS. Furthermore, familial factors might confound the association between maternal PCOS and neuropsychiatric disorders in offspring. Maternal BMI was available for birth cohort 2004–2014 only and there was no information on gestational weight gain. WIDER IMPLICATIONS OF THE FINDINGS This study provides further evidence that maternal PCOS and/or anovulatory infertility, independently and jointly with maternal obesity, perinatal problems, gestational diabetes and cesarean delivery, implies a broad range of adverse effects on offspring neurodevelopment. These findings may potentially help in counseling and managing pregnancies. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C and C.L.), THL Finnish Institute for Health and Welfare: Drug and pregnancy project [M.G.], the Swedish Research Council [2014-10171 to C.L.], the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council [SLL20170292 to C.L.], the Swedish Brain Foundation [FO2018-0141 and FO2019-0201 to C.L.]. X.C. was supported by the China Scholarship Council during her training in Karolinska Institute. L.K. was supported by the China Scholarship Council for his PhD study in Karolinska Institute. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER N/A.

Women with polycystic ovary syndrome (PCOS) in their reproductive years present with metabolic dysfunction and thus increased likelihood of long-term health consequences and diminished well-being in later life. Owing to their larger ovarian reserve, however, they may experience menopause at later age and protection from metabolic and cardiovascular diseases. Moreover, previous studies have indicated that late reproductive-aged, normal-weight women with PCOS do not seem to have the expected high risk for type 2 diabetes (T2D), as previously thought. Health-related quality of life, nevertheless, is decreased in women with PCOS up until late fertile age, warranting attention and actions from the health care personnel. Given conflicting reports regarding the risk of cardiovascular diseases, future research with well characterized and adequately sized PCOS populations are needed, as well as studies aiming to improve their health-related quality of life.

Context Combined oral contraceptives (COCs) alter inflammatory status and lipid metabolism. Whether different estrogens have different effects is poorly understood. Objective We compared the effects of COCs containing ethinyl estradiol (EE) or estradiol valerate (EV) and dienogest (DNG) with those containing DNG only on inflammation and lipid metabolism. Design Randomized, controlled, open-label clinical trial. Setting Two-center study in Helsinki and Oulu University Hospitals. Participants Fifty-nine healthy, young, nonsmoking women with regular menstrual cycles. Age, body mass index, and waist-to-hip ratio were comparable in all study groups at the beginning. Fifty-six women completed the study (EV + DNG, n = 20; EE + DNG, n = 19; DNG only, n = 17). Interventions Nine-week continuous use of COCs containing either EV + DNG or EE + DNG, or DNG only as control. Main Outcome Measures Parameters of chronic inflammation (high-sensitivity C-reactive protein [hs-CRP], and pentraxin 3 [PTX-3]) and lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides, and total cholesterol). Results Serum hs-CRP increased after 9-week use of EE + DNG (mean change ± standard deviation 1.10 ± 2.11 mg/L) compared with EV + DNG (−0.06 ± 0.97 mg/L, P = 0.001) or DNG only (0.13 ± 0.68 mg/L, P = 0.021). Also, PTX-3 increased in the EE + DNG group compared with EV + DNG and DNG-only groups (P = 0.017 and P = 0.003, respectively). In the EE + DNG group, HDL and triglycerides increased compared with other groups (HDL: EE + DNG 0.20 ± 0.24 mmol/L vs EV + DNG 0.02 ± 0.20 mmol/L [P = 0.002] vs DNG 0.02 ± 0.18 mmol/L [P = 0.002]; triglycerides: EE + DNG 0.45 ± 0.21 mmol/L vs EV + DNG 0.18 ± 0.36 mmol/L [P = 0.003] vs DNG 0.06 ± 0.18 mmol/L [P < 0.001]). Conclusions EV + DNG and DNG only had a neutral effect on inflammation and lipids, while EE + DNG increased both hs-CRP and PTX-3 levels as well as triglycerides and HDL. Trial Registration ClinicalTrials.gov NCT02352090

Context The role of androgen excess as a contributing factor to abnormal glucose metabolism (AGM) and insulin resistance in women remains controversial. Objective To investigate whether hyperandrogenemia (HA) estimated by serum testosterone (T) level and free androgen index (FAI) at ages 31 and 46 years is associated with insulin resistance, insulin secretion and AGM by age 46. Design Prospective study including 5889 females followed at ages 31 and 46 years. Setting General community. Participants Women with HA were compared with normoandrogenic women at ages 31 and 46 years. Intervention None. Main outcome measurements AGM, including prediabetes and type 2 diabetes mellitus, homeostatic model assessments of insulin resistance (HOMA-IR) and of pancreatic β-cell function (HOMA-B). Results At age 31 years, HA women displayed increased HOMA-IR (P = 0.002), HOMA-B (P = 0.007), and higher fasting insulin (P = 0.03) than normoandrogenic women after adjusting for body mass index (BMI). At age 46 years, there was a nonsignificant trend toward higher fasting glucose (P = 0.07) and glycated hemoglobin A1 (P = 0.07) levels in HA women. Women in the highest T quartile (odds ratio [OR] = 1.80; 95%CI, 1.15-2.82) at age 31 years and in the 2 highest FAI quartiles at ages 31 (Q4: OR = 3.76; 95% CI, 2.24-6.32) and 46 (Q4: OR = 2.79; 95% CI, 1.74-4.46) years had increased risk for AGM, independently of BMI, when compared with women in Q1. SHBG was inversely associated with AGM (at age 31 years: Q4: OR = 0.37; 95% CI, 0.23-0.60, at age 46 years: Q4: OR = 0.28; 95% CI, 0.17-0.44). Conclusion Hyperandrogenemia and low SHBG in early and middle age associates with AGM independently of BMI.

Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors (p = 0.030), deep myometrial invasion (p = 0.003), lymphovascular space invasion (p = 0.050), and large tumor size (p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women (p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium (p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 15% of the female population. The natural history of the syndrome is complex, including both androgen exposure in early life and adiposity-driven dysfunction involving also dysregulated, also involving altered hypothalamus–ovarian crosstalk. The manifestations can arise as early as childhood or puberty onward, suggesting that genetic susceptibility is an important etiological factor. In adulthood, women with PCOS present with reproductive, metabolic, and psychological health issues at a population-based level. Epidemiological studies on large datasets offer an excellent opportunity to evaluate health effects and costs related to the syndrome. Hospital or insurance-based datasets are also available; however, the results are not representative of the female population in the community. More longitudinal studies spanning from early childhood to late adulthood are needed to assess the long-term health impact and early manifestations of PCOS. Moreover, the identification of women with PCOS from large datasets can be expensive. Self-reported symptoms or PCOS diagnosis may offer a feasible approach.

ObjectivesTo identify the genetic determinants of pelvic organ prolapse (POP) and assess the predictive ability of polygenic risk scores (PRS) alone or in combination with clinical risk factors.DesignMeta-analysis of genome-wide association studies (GWAS) and PRS construction and validation.SettingGWAS summary statistics from three European datasets and individual-level data from Estonian Biobank, including phenotype questionnaire and measurement panel, together with follow-up data from linkage with national health-related registries.ParticipantsA total of 28,086 women with POP and 546,321 controls of European ancestry. Genetic risk scores were derived from a dataset of 20,118 cases and 427,426 controls of European ancestry and validated in a target dataset of 7,896 cases and 118,895 controls. Cases were defined using ICD codes and classical risk factors were derived from questionnaire data and ICD10 codes.ResultsThe identified novel loci reinforce the role of connective tissue abnormalities, urogenital tract development and point towards association with a range of cardiometabolic traits. A novel PRS combining 3,242,959 variants demonstrated that women in the top 5% have 1.63 (95% CI: 1.37 to 1.93) times the hazard of developing POP compared to the rest of the women. When analyzing PRS in incident POP, it showed similar predictive ability (Harrell C-statistic 0.583, sd=0.007) than five established clinical risk factors (number of children, body mass index (BMI), ever smoked, constipation and asthma) combined (Harrell C-statistic 0.588, sd=0.007) and demonstrated its incremental value in combination with these (Harrell C-statistic 0.630, sd=0.007).ConclusionsThe largest GWAS meta-analysis in POP to date identified 26 genetic loci which establish links between POP and connective tissue abnormalities, urogenital development and cardiometabolic health. We present a PRS for POP which provides the first potential tool for preventive strategies and early detection of higher risk susceptibility to POP including genetic risk factors.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 18% of women. Besides metabolic and fertility aspects, attention has lately been directed towards the detrimental effect of PCOS on psychological health. The objective of the study was to investigate whether women with PCOS are at higher risk for psychotic disorders. The study population derives from the Northern Finland Birth Cohort 1966 (N = 5889 women). The women with PCOS were identified by two simple questions on oligo-amenorrhea and hirsutism at age 31. Women reporting both symptoms were considered PCOS (N = 124) and asymptomatic women as controls (N = 2145). The diagnosis of psychosis was traced using multiple national registers up to the year 2016. Symptoms of psychopathology were identified using validated questionnaires at age 31. Women with PCOS showed an increased risk for any psychosis by age 50 (HR [95% CI] 2.99, [1.52–5.82]). Also, the risk for psychosis after age 31 was increased (HR 2.68 [1.21–5.92]). The results did not change after adjusting for parental history of psychosis, nor were they explained by body mass index or hyperandrogenism at adulthood. The scales of psychopathology differed between women with PCOS and non-PCOS controls showing more psychopathologies among the affected women. PCOS cases were found to be at a three-fold risk for psychosis, and they had increased psychopathological symptoms. PCOS should be taken into consideration when treating women in psychiatric care. More studies are required to further assess the relationship between PCOS and psychotic diseases.

Study question What is the role of androgen excess as a contributing factor to insulin resistance and abnormal glucose metabolism (AGM) in women? Summary answer There was a positive association between early adulthood hyperandrogenaemia with AGM. Serum SHBG levels could help identifying women at risk for disordered glucose metabolism. What is known already It is commonly recognised that insulin resistance induces compensatory hyperinsulinaemia which promotes ovarian androgen secretion. Studies in rodents have also suggested that testosterone causes prolonged activation of androgen receptor in pancreatic islet β-cells, inducing insulin hypersecretion and eventually secondary β-cell failure, thus predisposing to type 2 diabetes (T2D). However, the exact physiology behind the association between androgens, insulin resistance and T2D in women is not well understood. Many previously published studies are limited by cross-sectional study design, unrepresentative clinic populations, as well as variying steroid hormone measurement methods and definitions of androgen excess. Study design, size, duration A prospective longitudinal population-based cohort (n = 5,889) to investigate whether serum levels of testosterone (T, measured using LC-MS/MS) and free androgen index (FAI) at ages 31 and 46 associated with AGM at age 46 years. After exclusion of pregnant women, users of hormonal intrauterine device, contraceptive pills, hormone therapy, minipills and statins, there were 4,421 women at age 31 and 4,457 women at age 46. At age 46 a two-hour OGTT was performed in 2,780 women. Participants/materials, setting, methods Serum fasting glucose and insulin, insulin resistance (HOMA–IR) and pancreatic β-cell function (HOMA–B) assessments were performed at ages 31 and 46. Elevated T levels (age 31: >2.3nmol/l; age 46: >1.7nmol/l) were defined according to the 97.5% percentile. T2D diagnoses were gathered from postal questionnaire at age 46, and verified and completed from the hospital discharge and national medication reimbursement registers. Impaired fasting glucose, impaired glucose tolerance or T2D were categorised as AGM. Main results and the role of chance At age 31, hyperandrogenic (HA) women displayed increased insulin resistance estimated by HOMA-IR (1.35±0.96 vs. 1.03±0.44, P = 0.05), increased insulin secretion estimated by HOMA-B (115.05±34.67 vs. 99.25±25.47, P = 0.006), and higher fasting insulin level (10.48±7.54 mU/l vs. 7.93±3.42 mU/l, P = 0.034) compared with normoandrogenic (NA) women, after BMI adjustment. At age 46, HA women had comparable HOMA-B levels (98.04±60.03 vs. 96.27±65.89, P = 0.93) but their fasting glucose (5.57±1.06 mmol/l vs. 5.37±0.77 mmol/, P = 0.07) and glycated haemoglobin levels (37.47±7.83 mmol/mol vs. 36.18±4.99 mmol/mol, P = 0.07) tended to be higher. Women in the highest T quartile (Q4 odds ratio [OR]=1.77, 95%CI: [1.14–2.76]) and in the two highest FAI quartiles at age 31 (Q4: OR = 3.61 [2.16–6.03] and Q3: OR = 2.11 [1.24–3.59]) had increased risk for AGM at age 46, independently of BMI, when compared with women in the lowest quartile. Similarly, women in the two highest FAI quartiles at age 46 had increased risk for AGM (Q4: OR = 2.91 [1.82–4.64]) when compared with women in the lowest quartile, after BMI adjustment. The three highest sex hormone-binding globulin (SHBG) quartiles inversely associated with AGM, both at ages 31 and 46, independently of BMI (at age 31: Q4: OR = 0.38 [0.24–0.62], at age 46: Q4: OR = 0.27 [0.17–0.44]). Limitations, reasons for caution We used only serum T as a marker of HA, even though other androgens, such as androstenedione and adrenal androgens have a place in the evaluation of androgenicity in women. Further studies of other large populations are needed to confirm our results. Wider implications of the findings This is the first longitudinal, general population based study to confirm a positive association between early adulthood hyperandrogenaemia with AGM in middle adulthood independently of confounding factors. Our results further suggest that SHBG levels could help to identify women at risk for AGM. Trial registration number NA

Study question Can genome-wide association analysis unravel the biological underpinnings of PP and facilitate personalized risk assessment via genetic risk scores construction? Summary answer We unravel novel links with urogenital development and vascular health in PP and present polygenic risk score as a tool to stratify PP risk. What is known already Prolapse is characterized by a descent of the pelvic organs into the vaginal cavity. PP affects around 40% of women after menopause and is the main indication for major gynecological surgery, having an important health, social and economic burden. Although the etiology and biological mechanisms underlying PP remain poorly understood, prior studies suggest genetic factors might play a role. Recently, a genome-wide association study (GWAS) identified seven genome-wide significant loci, located in or near genes involved in connective tissue metabolism and estrogen exposure in the etiology of PP. Study design, size, duration We conducted a three-stage case-control genome-wide association study. Firstly, in the discovery phase, we meta-analyzed Icelandic, UK Biobank and the FinnGen R3 datasets, comprising a total of 20118 cases and 427426 controls of European ancestry. For replication we used an independent dataset from Estonian Biobank (7968 cases and 118895 controls). Finally, we conducted a joint meta-analysis, containing 28086 cases and 546321 controls, which is the largest GWAS of PP to date. Participants/materials, setting, methods We performed functional annotation on genetic variants unraveled by GWAS and integrated these with expression quantitative trait loci and chromatin interaction data. In addition, we looked at enrichment of association signal on gene-set, tissue and cell type level and analyzed associations with other phenotypes both on genetic and phenotypic level. Colocalisation analyses were conducted to help pinpoint causal genes. We further constructed polygenic risk scores to explore options for personalized risk assessment and prevention. Main results and the role of chance In the discovery phase, we identified 18 genetic loci and 20 genetic variants significantly associated with POP (p Limitations, reasons for caution This GWAS meta-analyses focused on European ancestry populations, which challenges the generalizability of GWAS findings to non-European populations. Moreover, this study included women with PP from population-based biobanks identified using the ICD-10 code N81, which limits analyses considering different disease stages and severity. Wider implications of the findings Our study provides genetic evidence to improve the current understanding of PP pathogenesis and serves as basis for further functional studies. Moreover, we provide a genetic tool for personalized risk stratification, which could help prevent PP development and improve the quality of a vast quantity of women. Trial registration number not applicable

Human fetal organogenesis is a complex process starting 4 weeks post conception. The gender specific gonads can be distinguished as early as by the GW 8 and the process is driven by the sex determining region on the Y-chromosome (SRY) among other genes that drive fetal testosterone and AMH effects. In the absence of anti-Müllerian hormone (AMH) the Müllerian ducts will develop to uterus and fallopian tubes, and without androgen influence the urogenital sinus will form as female external genitalia. Ovarian primordial follicles reach the highest number of 7 million around mid-gestation after which the number starts to decrease by means of apoptosis and only 2 million primordial follicles are left at the time of birth and less than half of million at puberty. The pituitary–ovarian axis of the fetus is activated at mid-gestation, after which levels of gonadotropins decrease towards the term, and become activated again after birth resulting in minipuberty. The quiescent period in gonadotrophins and sex steroid production remains during childhood ends before puberty as a consequence of maturation of the hypothalamus–pituitary–ovarian axis. During reproductive life around 400 follicles will ovulate with concomitant decrease of follicle pool through apoptosis. The follicle reserve is exhausted around the age of 50 years resulting into menopause.

BackgroundPolycystic ovary syndrome (PCOS) is a common, complex disorder, which should be recognized as a prominent health concern also outside the context of fertility. Although PCOS affects up to 18% of women worldwide, its etiology remains poorly understood. It is likely that a combination of genetic and environmental factors contributes to the risk of PCOS development. Whilst previous genome-wide association studies have mapped several loci associated with PCOS, analysis of populations with unique population history and genetic makeup has the potential to uncover new low frequency variants with larger effects. In this study, we leverage genetic information of two neighboring and well-characterized populations in Europe – Finnish and Estonian – to provide a basis for a new understanding of the genetic determinants of PCOS.Methods and FindingsWe conducted a three-stage case-control genome-wide association study (GWAS). In the discovery phase, we performed a GWAS comprising of a total of 797 cases and 140,558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2,812 cases and 89,230 controls. Finally, we conducted a joint meta-analysis of 3,609 cases and 229,788 controls from both cohorts.In total, we identified three novel genome-wide significant variants associating with PCOS. Two of these novel variants, rs145598156 (p=3.6 × 10−8, OR=3.01 [2.02-4.50] MAF=0.005) and rs182075939 (p=1.9 × 10−16, OR= 1.69 [1.49-1.91], MAF=0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2= 0.95) and a missense I157T (r2=0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, p= 1.7 × 10−8, OR=1.16 (1.10-1.23), MAF=0.44). We also replicated four previous reported associations near the genes ERBB4, DENND1A, FSHB and ZBTB16.ConclusionsWe identified three novel variants for PCOS in a Finnish-Estonian GWAS. Using isolated populations to perform genetic association studies provides a useful resource to identify rare variants contributing to the genetic landscape of complex diseases such as PCOS.

An association has been found between high anti-Müllerian hormone (AMH) levels during pregnancy and the development of polycystic ovary syndrome (PCOS)-like phenotypic traits in mouse offspring. The aim of this study was to determine whether AMH levels are associated with maternal testosterone levels, and whether high AMH concentration influences the risk of developing PCOS-related adverse pregnancy outcomes.Maternal serum AMH, testosterone and sex hormone binding globulin levels were measured in blood samples taken in early second-trimester pregnancies from women with PCOS (n = 159) and healthy controls matched for body mass index (n = 320). Possible associations with preeclampsia, gestational hypertension, gestational diabetes, preterm birth and birthweight was explored by logistic and linear regression models.Women with PCOS had higher AMH, higher total testosterone levels and higher free androgen index than controls (P0.001 for all three parameters). Among women with PCOS, high testosterone levels (B = 2.7; β = 0.26; P = 0.001) and low first trimester body mass index (B = -0.5; β = -0.17; P = 0.043) remained independently associated with AMH. High AMH levels were associated with decreased risk of gestational hypertension (adjusted OR 0.55; 95% CI 0.34 to 0.87), but no association was found with other adverse pregnancy outcomes or birthweight.Women with PCOS had higher AMH levels during pregnancy compared with controls, but high AMH was not associated with increased risk of adverse pregnancy outcomes or birthweight.

Background: Polycystic ovary syndrome (PCOS) has a prevalence of 8–13%. Given the prevalence, diverse health impacts and variation in care, rigorous evidence‐based guidelines are needed in PCOS management. This systematic review with meta‐analyses aimed to investigate the effect of the combined oral contraceptive pill (COCP) and/or metformin in the management of hormonal and clinical features of PCOS, to inform international guidelines. Methods: Electronic databases were searched systematically from inception until 11 January 2017 to inform the guideline process. Eligible studies were randomized controlled trials which investigated the effect of COCPs and/or metformin alone or combined on hormonal and clinical features in women with PCOS. Outcomes were prioritized as critical for informing a decision about an intervention or important or not important, according to GRADE. Articles were assessed by one author against selection criteria, in consultation with a second author. Data were double extracted independently by four authors, and data quality appraisal was completed. Meta‐analyses were conducted, where appropriate. Results: Fifty‐six studies were eligible for inclusion. Outcomes prioritized by women and health professionals included the following: irregular cycles, insulin resistance, weight, BMI, thromboembolic events and gastrointestinal effects. In low‐quality evidence in adolescents, meta‐analyses demonstrated that metformin was better than COCP for BMI (mean difference [MD] −4.02 [−5.23, −2.81], P < 0.001); COCP was better than metformin for menstrual regulation (MD −0.19 [−0.25, −0.13], P < 0.00001). In low‐quality evidence in adults, meta‐analyses demonstrated that metformin was better than placebo for BMI (MD −0.48 [−0.94, −0.02], P = 0.04); metformin was better than COCP for fasting insulin (MD 4.00 [2.59, 5.41], P = 0.00001), whereas COCP was better than metformin for irregular cycles (MD 12.49 [1.34, 116.62], P = 0.03). Combined oral contraceptive pill alone was better than the combination with an anti‐androgen for BMI (MD −3.04 [−5.45, −0.64], P = 0.01). Metformin was associated with generally mild gastrointestinal adverse events. Differences in statistical significance were observed when outcomes were subgrouped by BMI. Conclusions: This review identified that COCP therapy has benefits for management of hyperandrogenism and menstrual regulation. Metformin combined with the COCP may be useful for management of metabolic features. There is minimal evidence of benefits of adding an anti‐androgen to COCP therapy. Metformin alone has benefits for adult women for management of weight, hormonal and metabolic outcomes, especially for women with BMI ≥ 25 kg/m². There is inadequate evidence to suggest the optimal COCP formulation, or dosing regimen and formulation of metformin.

Background: Adiposity rebound (AR), the second BMI rise in childhood at around the age of 6 years, is associated with obesity and metabolic alteration in later life. Given that polycystic ovary syndrome (PCOS) has a strong metabolic component, early life growth patterns could reveal a risk of PCOS. Thus, we aimed to investigate the associations between age at AR and PCOS diagnosis and BMI later in life. Materials and methods: This study is part of a prospective, population-based longitudinal study, where women with PCOS diagnosis by age 46 (n = 280) were compared with asymptomatic women (CTRLs, n = 1573). Weight and height data from birth to age 13 years, at age at menarche, and at ages 31 and 46 years were analyzed Results: Women with PCOS had lower birth weight (3357 +/- 477 vs. 3 445 +/- 505 g, p

Context Despite the gut microbiome being widely studied in metabolic diseases, its role in polycystic ovary syndrome (PCOS) has been scarcely investigated. Objective Compare the gut microbiome in late fertile age women with and without PCOS and investigate whether changes in the gut microbiome correlate with PCOS-related metabolic parameters. Design Prospective, case–control study using the Northern Finland Birth Cohort 1966. Setting General community. Participants A total of 102 PCOS women and 201 age- and body mass index (BMI)-matched non-PCOS control women. Clinical and biochemical characteristics of the participants were assessed at ages 31 and 46 and analyzed in the context of gut microbiome data at the age of 46. Intervention (s): None Main outcome measure(s) Bacterial diversity, relative abundance, and correlations with PCOS-related metabolic measures. Results Bacterial diversity indices did not differ significantly between PCOS and controls (Shannon diversity P = .979, unweighted UniFrac P = .175). Four genera whose balance helps to differentiate between PCOS and non-PCOS were identified. In the whole cohort, the abundance of 2 genera from Clostridiales, Ruminococcaceae UCG-002, and Clostridiales Family XIII AD3011 group, were correlated with several PCOS-related markers. Prediabetic PCOS women had significantly lower alpha diversity (Shannon diversity P = .018) and markedly increased abundance of genus Dorea (false discovery rate = 0.03) compared with women with normal glucose tolerance. Conclusion PCOS and non-PCOS women at late fertile age with similar BMI do not significantly differ in their gut microbial profiles. However, there are significant microbial changes in PCOS individuals depending on their metabolic health.

Introduction Endometriosis is a common gynecological condition causing chronic pain and infertility. Only limited data exists on body size during childhood and in adolescence in affected women. A leaner body shape has been associated with endometriosis in adults. However, longitudinal follow-up data from birth to adulthood are lacking. The aim of this study was to assess the association between body size and endometriosis from birth to age 46 years. We also performed in-depth analysis of the endometriosis subtypes. Material and methods This was a population-based study including 96% of the children born in Northern Finland in 1966. Endometriosis case identification was based on 1) the World Health Organization's International Statistical Classification of Diseases -code documentation from national hospital discharge registers and 2) self-reported diagnosis. A total of 348 women with endometriosis (203 in subtype analysis) and 3487 women without endometriosis were identified. Pregnancy, birth and growth data up-to adolescence were collected from welfare clinical records. Follow-up data of the Northern Finland Birth Cohort 1966 were collected at ages 14, 31, and 46 through postal questionnaires and clinical examinations and included height, weight, and waist and hip circumference measurements. The associations between endometriosis and body size was assessed using logistic regression models. Results The body sizes in childhood and adolescence were comparable between women developing endometriosis and those not developing endometriosis. On average, the risk for endometriosis was 2% lower for every kilogram of weight (OR: 0.98, 95% CI: 0.97-1.00) and 6% lower for every body mass index unit (OR: 0.94, 95% CI: 0.90-0.99) at age 31. By age 46, a lower risk for peritoneal endometriosis was observed with greater weight (OR: 0.95, 95% CI: 0.92-0.98), weight gain from age 14 to age 46 (OR: 0.97, 95% CI: 0.93-1.00), body mass index (OR: 0.90, 95% CI: 0.82-0.98), waist circumference (OR: 0.95, 95% CI: 0.92-0.99), and waist-hip ratio (OR: 0.41, 95% CI: 0.21-0.78). Conclusions This study provides further evidence of the associations between endometriosis and body size and adiposity, specifically in women with peritoneal endometriosis. The associations are evident in adulthood but not in childhood or adolescence.

The purpose of this prospective, population-based cohort study was to evaluate the roles of polycystic ovary syndrome (PCOS), obesity, weight gain, and hyperandrogenemia in the development of hypertensive disorders of pregnancy (HDP) through fertile age both in PCOS and in non-PCOS women. The study population—NFBC1966 (Northern Finland Birth Cohort 1966)—allowed a long-term follow-up of women from age 14 until 46 years who developed HDP (n=408) or did not (n=3373). HDP diagnosis was confirmed by combining hospital discharge records, data from Finnish Medical Birth Registers, and the questionnaire data at age 46. Women with self-reported PCOS (srPCOS; n=279), defined by both oligo-amenorrhea and hirsutism at age 31 or with PCOS diagnosis by age 46, were compared with women without reported PCOS (n=1577). Women with srPCOS had an increased HDP risk (odds ratio, 1.56 [95% CI, 1.03–2.37]), but the association disappeared after adjustment for body mass index. In women with srPCOS and HDP, body mass index increased from age 14 to 46 significantly more than in srPCOS women without HDP (median [interquartile range], 9.82 [6.23–14.6] and 7.21 [4.16–10.5] kg/m 2 , respectively; P 2 ; P 2 ; P

ObjectivesAltered intestinal permeability and gut barrier dysfunction have been suggested to play a role in the pathogenetic mechanism of polycystic ovary syndrome (PCOS), the most common endocrine and metabolic condition in reproductive-aged women. However, data on intestinal permeability and dysbiosis of the gut microbiota in PCOS is still limited, with conflicting results. To this end, the concentrations of gastrointestinal permeability and gut dysbiosis markers were analysed in women with PCOS.DesignCase–control study.SettingGeneral community.Participants104 women with PCOS and 203 body mass index (BMI) matched control women at age 46.Primary and secondary outcome measuresSerum levels of zonulin, fatty acid-binding protein 2 (FABP2), urinary levels of indican, and hormonal and metabolic parameters.ResultsSerum levels of zonulin (128.0±17.0 vs 130.9±14.0 ng/mL, p=0.13) and FABP2 (1.5±0.9 vs 1.5±0.7 ng/mL, p=0.63) and urinary levels of indican (9.5±5.5 vs 8.4±4.2 mg/dL, p=0.07) were comparable in women with PCOS and controls in the whole study population. Likewise, when the study population was divided into different BMI groups as normal weight, overweight and obese, the levels of the above markers were comparable between the study groups. After BMI adjustment, zonulin levels correlated with the levels of high-sensitivity C reactive protein and homoeostasis model assessment of insulin resistance (pConclusionsIntestinal permeability markers zonulin and FABP2, and the dysbiosis marker indican do not seem to be altered in women with PCOS at age 46 compared with BMI-matched controls. Serum zonulin levels correlated with BMI, insulin resistance and inflammatory marker levels, but did not segregate women with PCOS and controls. This suggests that metabolic factors, but not PCOS per se, is the driving force of dysbiosis in premenopausal women with PCOS.

Purpose Populations living in the Nordic countries are at high risk for vitamin D (VitD) deficiency or insufficiency. To reduce the risk, nationwide interventions based on food fortification and supplementation are being implemented. However, there is limited evidence about the impact of such public health campaigns on target populations. Methods We studied an unselected sample of 3650 participants (56.2% females) from the longitudinal Northern Finland Birth Cohort 1966 with repeated measures of serum 25-hydroxyvitamin D [25(OH)D] at ages 31 (1997) and 46 (2012–2013). Timepoints corresponded to the period before and during the food fortification. We examined the effect of VitD intake from the diet and supplementation, body mass index and previous 25(OH)D concentration on 25(OH)D concentration at 46 years using a multivariable linear regression analysis. A 25(OH)D z score adjusted for sex, season, latitude and technical effect was used in the analysis. Results We observed an increase of 10.6 nmol/L in 25(OH)D, when the baseline 25(OH)D was 54.3 nmol/L. The prevalence of serum 25(OH)D below Conclusion Our results demonstrated the positive impact of the fortification programme on VitD status in middle-aged population.

Objective Obesity is considered to be the strongest predictive factor for cardio-metabolic risk in women with polycystic ovary syndrome (PCOS). The aim of the study was to compare blood pressure (BP) in normal weight women with PCOS and controls matched for age and BMI. Methods From a Nordic cross-sectional base of 2615 individuals of Nordic ethnicity, we studied a sub cohort of 793 normal weight women with BMI 2 (512 women with PCOS according to Rotterdam criteria and 281 age and BMI-matched controls). Participants underwent measurement of BP and body composition (BMI, waist-hip ratio), lipid status, and fasting BG. Data were presented as median (quartiles). Results The median age for women with PCOS were 28 (25, 32) years and median BMI was 22.2 (20.7, 23.4) kg/m2. Systolic BP was 118 (109, 128) mmHg in women with PCOS compared to 110 (105, 120) mmHg in controls and diastolic BP was 74 (67, 81) vs 70 (64, 75) mmHg, both P < 0.001. The prevalence of women with BP ≥ 140/90 mmHg was 11.1% (57/512) in women with PCOS vs 1.8% (5/281) in controls, P < 0.001. In women ≥ 35 years the prevalence of BP ≥ 140/90 mmHg was comparable in women with PCOS and controls (12.7% vs 9.8%, P = 0.6). Using multiple regression analyses, the strongest association with BP was found for age, waist circumference, and total cholesterol in women with PCOS. Conclusions Normal weight women with PCOS have higher BP than controls. BP and metabolic screening are relevant also in young normal weight women with PCOS.

STUDY QUESTION What is the association between childhood and adolescent BMI and reproductive capacity in women? SUMMARY ANSWER Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS). WHAT IS KNOWN ALREADY Girls with obesity (BMI (kg/m2)>95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited. STUDY DESIGN, SIZE, DURATION A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth register. Decreased fecundability was defined at age 31 years as time to achieve pregnancy over 12 months. Logistic regression analyses were conducted with adjustments for marital status, education level and smoking at age 31 years. Women with PCOS were excluded from stratification-based sensitivity analyses. Obesity at a specific age group was defined by having at least one BMI value above the 95th percentile during the related period. MAIN RESULTS AND THE ROLE OF CHANCE BMI at the age of AR (5–7 years) was not associated with fertility outcomes after adjustments, but girls with AR LIMITATIONS, REASON FOR CAUTION Despite a high participation rate throughout the follow-up, some growth data for children over the different age groups were missing. Infertility outcomes were self-reported. A potential over-diagnosis of obesity may have reduced the significance of the association between childhood obesity and fertility outcomes, and the diagnosis of PCOS was self-reported. WIDER IMPLICATIONS OF THE FINDINGS This study supports previous results showing that girls with obesity in late childhood and in adolescence displayed reduced fertility and an increased risk of remaining childless in adulthood, independently of marital history and PCOS in adulthood. These findings corroborate the body of evidence for a causal relation between early adiposity and the reproductive functions in women. We recommend reinforcing the prevention of obesity in school-age girls to reduce the risk of impaired reproductive functions. STUDY FUNDING/COMPETING INTEREST(S) NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. The Finnish Medical Foundation, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, Biocenter Oulu, University Hospital Oulu and University of Oulu (75617), Jalmari ja Rauha Ahokkaan säätiö, The Finnish Medical Foundation, Medical Research Center Oulu, National Institute for Health Research (UK). M. R. J., S. S. and R. N. received funding by the Academy of Finland (#268336) and the European Union’s Horizon 2020 research and innovation program (under Grant agreement no. 633595 for the DynaHEALTH action and GA 733206 for LifeCycle). The funders had no role in study design, in the collection, analysis and interpretation of the data, in the writing of the article and in the decision to submit it for publication. The authors have no conflict of interest to disclose. TRIAL REGISTRATION NUMBER N/A.

Hyperandrogenic women with PCOS show disrupted decidualization (DE) and placentation. Dihydrotestosterone (DHT) is reported to enhance DE in non-PCOS endometrial stromal cells (eSCCtrl); however, this has not been assessed in PCOS cells (eSCPCOS). Therefore, we studied the transcriptome profile of non-decidualized (non-DE) and DE eSCs from women with PCOS and Ctrl in response to short-term estradiol (E2) and/or progesterone (P4) exposure with/without (±) DHT. The non-DE eSCs were subjected to E2 ± DHT treatment, whereas the DE (0.5 mM 8-Br-cAMP, 96 h) eSCs were post-treated with E2 and P4 ± DHT, and RNA-sequenced. Validation was performed by immunofluorescence and immunohistochemistry. The results showed that, regardless of treatment, the PCOS and Ctrl samples clustered separately. The comparison of DE vs. non-DE eSCPCOS without DHT revealed PCOS-specific differentially expressed genes (DEGs) involved in mitochondrial function and progesterone signaling. When further adding DHT, we detected altered responses for lysophosphatidic acid (LPA), inflammation, and androgen signaling. Overall, the results highlight an underlying defect in decidualized eSCPCOS, present with or without DHT exposure, and possibly linked to the altered pregnancy outcomes. We also report novel factors which elucidate the mechanisms of endometrial dysfunction in PCOS.